FI106198B - A process for the preparation of therapeutically useful 3-substituted 2-carboxyindole derivatives - Google Patents

Description

! 106198

This invention relates to a process for the preparation of indole derivatives 5, and to a therapeutically useful 3-substituted 2-carboxyindole derivative. In particular, it relates to a process for the preparation of indole derivatives which are potent and selective antagonists of excitatory amino acids.

U.S. Patent No. 4,960,786 discloses that certain known 2-carboxylindole derivatives are antagonists of excitatory amino acids. EP-A-0 396 124 also teaches that certain 2-carboxylindole derivatives are therapeutically effective in treating central nervous system disorders due to neurotoxic injury or neurodegenerative disorders.

We have now found a new group of 2-carboxylindole derivatives which have a very potent and selective antagonism of strychnine at the glycine binding site located in the NMDA-re-20 receptor complex.

The invention thus relates to a process for the preparation of a compound of formula (I)

Cl * ... · 2 5 ^ aconhr2: · (I) ci h ··· · · · · · · · 30 or a salt thereof, or a metabolically labile ester wherein A represents an ethynyl group, or optionally substituted ethenyl, or a cyclopropyl group; R 2 · · ·; ** represents an optionally substituted phenyl group.

The compounds of formula (I) may exist in more than one isomeric form. Thus, when the group of ((aaaaaaaa <RTI ID = 0.0> a </RTI> <RTIgt; 1 · a »a </RTI> <RTIgt; 106198 </RTI> A in the compounds of formula (I) has an optionally substituted ethenyl group, cis and trans isomers may exist; such isomers and mixtures thereof.

For medical use, the salts of the compounds of formula (I) must be their physiologically acceptable salts. However, other salts may be useful in the preparation of compounds of formula (I) or physiologically acceptable salts thereof. Therefore, unless otherwise stated, references to salts include both physiologically acceptable salts and physiologically unacceptable salts.

Suitable physiologically acceptable salts of the compounds of the invention include base addition salts and, where appropriate, acid addition salts.

Suitable base addition salts of the compounds of formula (I) include alkali metal or alkaline earth metal salts such as sodium, potassium, calcium and magnesium salts and amino acids (eg, lysine and arginine) and organic bases (eg, procaine, phenylbenzylamine). ethanolamine, diethanolamine and N-methylglucose amine).

It will be appreciated that the compound of formula (I) may be formed in vivo by metabolism of a suitable precursor.

Such precursors may be, for example, physiologically acceptable metabolically labile esters of the compounds of general formula (I) * .1.1. These can be formed by blocking, for example, any amount of carboxylic acid group present in the original molecule of formula (I), where necessary protecting any .2 3 ·. other reactive group present in the molecule and • «·. ···. then protection is removed, if necessary. Examples of such metabolically labile esters include C 1-6 -alk 'alkyl esters, e.g., methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g.

106,198 aminoethyl, 2- (N, N-diethylamino) ethyl, or 2- (4-morpholino) ethyl esters) or acyloxyalkyl esters such as acyloxymethyl. - or 1-acyloxyethyl, e.g., pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 5-acetoxyethyl, 1-methoxy-1-methylethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyl-oxymethyl, 1- isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, 10 1 -cyclohexyloxycarbonyloxyethyl, 1- (4-tetrahydropyranyloxycarbonyloxy) -ethyloxy-1-cyclohexyloxy-1

Preferred metabolically labile esters of the compounds of formula (I) include C 1-4 alkyl esters, more particularly methyl or ethyl esters, aminoalkyl esters, more particularly 2- (4'-morpholino) ethyl or acyloxyalkyl esters, e.g. acetoxymethyl, pivaloyloxymethyl, -cyclohexyloxycarbonyloxyethyl or 1- (4-tetrahydropyranyloxycarbonyloxy) ethyl esters.

The compounds of formula (I) and their salts and metabolically labile esters may form solvates and, e.g., hydrates, and the invention includes a process for the preparation of such solvates.

The term alkyl, as used herein, refers to a group consisting of • «* · ♦« 'or a part of a group of straight-chain or branched-chain alkyl of 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl. , isobutyl, secondary isobutyl and tertiary butyl.

The term halogen means fluorine, chlorine or bromine.

. . ···. The term optionally substituted ethenyl means • ·. ···. or an ethenyl or 1-methylethenyl group.

The term substituted phenyl means a phenyl group substituted with up to three substituents · ... · 35 selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C · 106198 amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, nitro, amino, SO4 and CORx, when more than one substituent is present these may be the same or different.

When A is an optionally substituted ethenyl group, it is preferably in the E position.

When R 2 is a substituted phenyl group, the phenyl group is preferably substituted by one or two groups selected from alkoxy, alkyl, amino, C 1-10 alkylamino, dialkylamino, fluoro, chloro, hydroxy, nitro, trifluoromethyl or COR-1 wherein R x is hydroxy or methoxy.

A preferred class of compounds of formula (I) are those compounds wherein R 2 is phenyl or phenyl substituted with one or two groups selected from fluoro, trifluoromethyl, alkyl eg methyl or isopropyl, hydroxy, alkoxy or nitro, or more particularly when R 2 is phenyl.

A preferred class of compounds of formula (I) are those compounds wherein A represents a cyclopropyl group, or more particularly an ethynyl group or 1-methyl-ethenyl.

Preferred compounds of the formula (I) wherein A represents an unsubstituted ethenyl group include those compounds wherein the group A is in the trans (E) position. Particularly preferred compounds within this group of preferred compounds * ·· are those wherein R 2 is a phenyl group substituted with one or two groups selected from fluorine, trifluoromethyl, methyl, isopropyl, hydroxy, alkoxy. e.g., methoxy or ethoxy, or nitro.

• · • ·

A particularly preferred compound of the invention, ♦ ♦ due to its particularly potent and selective action on strychnine insensitive glycine binding site, together with the very favorable biocompatibility of 106198 (E) -3- [2- (Phenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid, its physiologically acceptable salts and its metabolically labile esters. Preferred salts of this compound are its potassium salt and especially its sodium salt. Preferred metabolically labile esters of this compound are its ethyl and 2- (4-morpholino) ethyl esters.

Preferred compounds further include 3- [2- (phenylcarbamoyl) ethynyl] -4,6-dichloroindole-2-carboxylic acid, physiologically acceptable salts thereof, and metabolically labile esters; 3- [2- (phenylcarbamoyl) propenyl] -4,6-dichloroindole-2-carboxylic acid, its physiologically acceptable salts and its metabolically labile esters.

Other particularly preferred compounds are: (E) -3- [2- (4-ethoxyphenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid; (E) -3- [2- (2-Hydroxy-5-nitrophenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid; 20 (E) -3- [2- (2-Methyl-4-methoxyphenylcarbamoyl) -ethenyl] -4,6-dichloro-indole-2-carboxylic acid; (E) -3- [2- (2-Isopropyl-phenylcarbamoyl) -ethenyl] -4,6-dichloro-indole-2-carboxylic acid; (') - (E) -3- [2- (2,4-Difluorophenylcarbamoyl) ethenyl] -? - 4,6-dichloroindole-2-carboxylic acid; •' (E) -3- [ 2- (3,4-Dimethoxyphenylcarbamoyl) -ethenyl-4,6-dichloro-indole-2-carboxylic acid and their physiologically acceptable salts, e.g. Lysium salts and their metabolically labile esters.

Compounds of formula (I) and their physiological ···. the acceptable salts are the excitatory amino acids.

H1 antagonists. More specifically, they are potent antagonists of strychnine insensitive glycine binding site associated with the NMDA receptor complex. For example, at 3:35, they are potent antagonists of the NMDA receptor complex-? In addition, the compounds of the invention have a favorable activity profile including good biocompatibility. These compounds are thus useful in the treatment or prevention of neurotoxic Vau-5 or neurodegenerative diseases. The compounds are thus useful in the treatment of neurotoxic injury following stroke, thrombosis, cerebral haemorrhage, cerebrovascular accident, hypoglycemia, pineapple 10, hypoxia, hypoxia, postpartum. The compounds are useful in the treatment of chronic neurodegenerative diseases such as: Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, glutaranal sciatica, multi-infarct dementia, epilepsy, congestive lesions (eg spinal cord injury), eg. , Down syndrome, epilepsy, multiple sclerosis, depression, anxiety, pain, neurogenic bladder, irritable bladder disorder, drug dependence including withdrawal symptoms of alcohol, cocaine, opiates, nicotine and benzodiazepine.

The potent and selective activity of the compounds of the invention at the strychnine insensitive glycine-25 binding site present in the NMDA receptor compound can be readily determined by conventional assay methods. Thus, the ability to bind to a strychnine-sensitive glycine binding site was determined using the ···· method described by Kishimoto H. et al. J.

30 Neurochem 1981, 37 1015-1024. The selectivity of the activity of the compounds of the invention for the strychnine-sensitive glycine binding site was determined by assaying other known ionic excitatory amino acid receptors. Thus, it was found that the compounds prepared according to the invention have little or no affinity for the cainic acid (kainate) receptor, the α-amino- 3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) with a resptor at the NMDA binding site.

The compounds of the invention have also been found to inhibit NMDA-induced seizures in mice using the method described by Chiamulera et al. Psychopharmacology (1990) 102, 551-552.

The neuroprotective effect of the compounds of the invention has also been demonstrated in a midbrain arterial occlusion preparation in a mouse using the method described by Chiamulera et al. European Journal of Pharmacology 216: 335-336 (1992). The compounds were active when administered either before or after ischemia.

The compound of general formula (I) and / or a physiologically acceptable salt or a metabolically labile ester thereof prepared by the process of the invention can be used in therapy, and in particular for use as a medicament that counteracts the effects of excitatory amino acids in the NMDA receptor complex.

The compound of general formula (I) and / or the physiologically acceptable salt or metabolically labile ester thereof prepared by the process of the invention may also be used in the preparation of a medicament which is opposed to the effects of excitatory amino acids in the NMDA receptor complex.

Also disclosed herein is a method for counteracting the effects of excitatory amino acids in the plexus NMDA receptor, · 1 · ·, characterized by administering to a patient in need thereof an antagonistic amount of a compound of formula (I) and / or a physiologically acceptable salt thereof or a metabolically labile ester thereof.

It will be understood by one of ordinary skill in the art that reference herein to treatment includes prophylaxis as well as the treatment of established conditions or symptoms.

• 9 9 «« · • I «« «« • • · · • s 106198

It will further be appreciated that the amount of the compound required for treatment by the method of the invention may be varied depending upon the nature of the condition being treated, the mode of administration and the age of the patient, and will ultimately depend on the judgment of the attending physician. Generally, doses used in the treatment of an adult human will typically range from 2 to 800 mg per day, depending on the route of administration.

Thus, for parenteral administration, the daily dose will typically be in the range of 20 to 100 mg, preferably 60 to 80 mg per day. The daily dose for oral administration is typically in the range of 200 to 800 mg, e.g., 400 to 600 mg per day.

The desired dose may be practically administered in a single dose or in divided doses in appropriate aliquots of 15, e.g., two, three, four or more sub-doses per day.

While it is possible, for therapeutic use, to administer a compound prepared according to the invention as a raw chemical, it is preferable to administer the active ingredient as a pharmaceutical composition.

Further provided herein is a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, or a metabolically Ia carbon thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and / or prophylactic ingredients. . The carrier (s) must be "acceptable" so that they are compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The compositions include those in a form specially formulated for oral administration, the buccal cavity, the gastrointestinal tract, by inhalation or insufflation, implantation, or injection. through the rectum. Gastrointestinal administration is · · · 35 inexpensive.

• · ♦ • · · ♦ ♦ ♦ ♦ 106 106 9 106198

Tablets or capsules for oral administration may contain conventional excipients such as binders, e.g., syrup, acacia gum, gelatin, sorbitol, tragacanth, starch mucilage or polyvinylpyrrolidone; excipients such as lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants e.g. magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrating agents, e.g. potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulfate. The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle. Such liquid preparations may contain conventional additives such as suspending agents, e.g., sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible; emulsifiers, e.g. lecithin, sorbitane monooleate or acacia; non-aqueous

• «I

·., / Solvents (which may include edible oils), e.g.

25 almond oil, fractionated coconut oil, oily esters, · 1 · ': propylene glycol or ethyl alcohol; and preservatives • · e.g. methyl or propyl p-hydroxybenzoate or as · · · 1 corbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration, the composition may be in the form of tablets or dragees formulated in a conventional manner.

* Such a composition may be formulated for administration • · ·, ···. 35 from the gastrointestinal tract by injection or continuous infusion. 411 • 414 • «♦ • 10 106198. Compositions for injection may be presented in unit dosage form in ampoules or in multi-dose containers with added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous solvents, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile 10 pyrogen-free water, before use.

For administration by inhalation, the compounds of the invention are substantially delivered in aerosol spray form from pressure vessels using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dosage form can be determined by using a valve to deliver a metered amount.

Alternatively, for administration by inhalation or killing, the compounds of the invention may be in the form of a dry powder composition, e.g., as a mixture of a compound and a suitable carrier such as lactose or starch. The powder composition may be in 25 unit dosage forms, e.g., in capsules or cachets,

4 I I

such as gelatin, or blister packs, which may be delivered with an inhaler or nebulizer.

The above composition may also be formulated as a stock preparation. Such long acting formulations may be administered by implantation (e.g.

• 1 * ··· 1 subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compositions may be formulated, e.g.

With suitable polymeric and hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ionic ·

IM

10 106198 as exchange resins, or as sparingly soluble derivatives, e.g. as a sparingly soluble salt.

The compositions may contain between 0.1 and 99% of the active ingredient, usually between 30 and 95% for tablets and capsules, and between 3 and 50% for liquid preparations.

The compounds of general formula (I) and their salts may be prepared by the general methods set out below. In the following description, the groups R, Rx and R210 are as defined for the compounds of formula (I) unless otherwise stated.

Compounds of formula (I) wherein A is an optionally substituted ethenyl group may be prepared from a compound of formula (II) wherein R 3 is a carboxyl protecting group

Cl

IxHO

di)

20 ^ 1 H

by reacting this with a suitable phosphorus ylide, * 'i capable of converting a CHO group into ACONHR2, wherein • i - 25 R2 has the same meaning as above for formula (I), and • ti if necessary, removing the carboxyl protecting group; .

** "Suitable carboxyl protecting groups include allyl, alkyl, trichloroalkyl, trialkylsilyl, or aryl methyl groups such as benzyl, nitrobenzyl or trityl.

»·· In one embodiment of this method, this • *»,. the reaction may be carried out using the phosphorus ylide of the formula (III) ·····························•••••••••• ♦ 12 106198 (r5) 3P = CHCONHR2 (III) wherein R5 is an alkyl or phenyl group and R2 is as defined above.

The reaction is carried out in an aprotic solvent such as acetonitrile or ether such as 1,4-dioxane and preferably by heating, for example at 40-120 ° C.

In another embodiment of the process, the reaction is carried out using a phosphoryl ylide of formula (IV) 10 (R 70) 20 P = CCONHR 2 (IV) k 15 wherein R 6 represents hydrogen or methyl. R 7 represents C 1-4 alkyl, and R 2 has the same meaning as above.

The reaction is carried out in an aprotic solvent such as tetrahydrofuran and optionally by heating.

Compounds of formula (I) wherein A is a cyclopropyl-20-yl group may be prepared by treatment of an olefin of formula (V). ^ ch = ch2 r ^ jT '^ pC02r, n2 = chconhr2 25 —m

: Y: Cl M

•; (V) wherein R 1 is as defined above for a diazo derivative of formula (VI) wherein R 2 is as defined above followed by a trimethylsilyl ethoxymethyl group. .. * is removed, and if necessary or desired, by removal of the carboxyl protecting group R 3. The reaction is carried out in a solvent such as 1,2-dimethoxyethane and a rhodium (II) catalyst such as •, ···. 35 in the presence of rhodium acetate or pivalate.

• · «· · 4 * 4 • · · · · 13 106198

Compounds of formula (I) wherein A is an ethynyl group may be prepared by reacting an alkyne of formula (VII)

Cl I

Wherein R 2 has the same meaning as above for Formula (I) and R 9 represents (CH 3) 3 SiCH 2 CH 2 OCH 2 - by reaction with hydrochloric acid in ethanol followed by reaction of the product with a suitable base such as lithium hydroxide.

Compounds of formula (I) or protected derivatives thereof may be converted to other compounds of the invention.

Thus, the compounds of formula (I) wherein A is an unsubstituted ethenyl group having a cis configuration can be prepared from the corresponding compound of formula (I) wherein A is an ethynyl group by reduction with hydrogen and using palladium on calcium carbonate / lead oxide. ·. as a catalyst.

In any of the above reactions, the carboxylic protecting group R 3 may be removed by conventional methods to remove such groups. Thus, the group R3 can be removed by hydrolysis using alkali metal hydroxide

• M

e.g. lithium hydroxide in a solvent such as ethanol, · · ·; Followed by addition of a suitable acid, e.g. hydrochloric acid, to give: ***: the corresponding free carboxylic acid.

• · ·

Physiologically acceptable salts of the compounds of formula (I) may be prepared by treating an 'acid with a suitable base, e.g., an alkali metal or an alkaline earth hydroxide, in a suitable solvent, such as an alkanol, e.g. methanol.

Metabolically labile esters of the compounds of formula (I) may be prepared by esterification of a carboxylic acid group or a salt thereof, or by transesterification using conventional methods. Thus, for example, acyloxyalkyl esters may be prepared by reacting the free carboxylic acid or a salt thereof with the corresponding acyloxyl halide in a suitable solvent, such as dimethylformamide. For the esterification of the free carboxyl group, this reaction is preferably carried out in the presence of a quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride.

Aminoalkyl esters can be prepared by transesterification of the corresponding alkyl ester e.g. methyl or ethyl ester by reaction with the corresponding aminoalkanol at elevated temperature e.g. 50-150 ° C.

Compounds of formula (II) wherein R3 is a carboxyl protecting group may be prepared by treating the corresponding indole (VIII)

Cl —COzR, · ::> JL u — m {viii>

· 1 ··. 25 X

Cl, 1 N-methyl formanilide and phosphorus oxychloride in a solvent such as 1,2-dichloroethane.

♦ ♦ 1 *** 30 Compounds of formula (V) can be prepared by treating the corresponding compound of formula (II) with a reagent capable of introducing a CH = CH 2 group into the molecule.

• »1

Thus, by reacting the compound of formula (II) with the triphenylphosphine derivative Ph3P + CH3Br in the presence of a suitable base such as butyllithium in an aprotic solvent, the corresponding compound is obtained. a compound of formula (V).

Compounds of formula (VII) may be prepared by reacting bromic acid (IX) 5

Cl 1 jteCBc ιΊ- ~ (IX)

10 Cl I * H

Rg is reacted with the appropriate isocyanate R2NCO in the presence of a suitable base such as t-butyl lithium and an aprotic solvent such as tetrahydrofuran and then reacting the crude reaction product with trimethylsilyldiazole ((CH3) 3 SiCHN2). Bromic acid (IX) can be prepared from indole (II) using the following reaction scheme.

• «• • • • • • • • • • • • • • • • • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · • · Λ I I (((t t t t 106 106 106 106 16 106198

Cl

Cl _x * ». - · ci * · C1 H (XII) (W)

ÄC _ & C

R 9 Cl I

Rg 15 W (XI)

Cl 1 .föCBr 20 IM il

The compounds of formula (IX) may be prepared by alkaline hydrolysis of the corresponding ester (X). The ester "" f "(X) can be prepared from the corresponding dibromoethylene (XI) ♦ · · 30 by reacting it with a suitable base such as lithium bis-trimethylsilylamide in a suitable solvent such as ether e.g. tetrahydrofuran. Dibromoethylene · · * (XI) can be prepared from the corresponding aldehyde (XII) by reacting it with triphenylphosphine and carbon tetrachloride in a solvent such as dichloromethane.

«4« 44 4 · · 4 «17 106198 The N-protected indole (XII) can be prepared from the indole (II; R 4 = H) by reacting it with trimethylsilyl ethoxymethyl chloride with a base such as sodium bis-trimethylsilylamide in a polar aprotic solvent such as n, n-dimethylformamide.

The indoles of formula (VIII) are either known compounds or may be prepared by methods analogous to those described for known compounds.

In order that the invention may be more fully understood, the following examples are given by way of illustration only.

The Intermediates and Examples are valid unless otherwise stated: Melting points (m.p.) were determined on a Gallenkamp melting point apparatus and are uncorrected. All temperatures refer to Celcius degrees. Infrared spectra were measured on an FT-IR instrument. Proton magnetic resonance spectra (1 H-NMR) were measured at 300 MHz, chemical shifts are reported in ppm down (d) from Me4Si used as internal standard, and are denoted as singlets (s), doublets (d). ), doublets of doublets (dd), 2 0 triplets (t), quartets (q), or multiplets (m). Column chromatography was performed on silica gel (Merck AG, Darmstadt, Germany). The following abbreviations are used throughout the text: EA = ethyl acetate, CH = cyclohexane, DCM = dichloromethane, BDU = 1,8-diazabicyclo [5.4.0] undec-7-: ... · 25 ene, DMF = Ν, Ν- dimethylformamide, THF = tetrahydrofuran • · ϊ.ϊ.ϊ, LiOH.H20O = lithium hydroxide monohydrate. The road refers to thin layer chromatography on silica gel plates. The solvents were dried over anhydrous sodium sulfate.

«··· Intermediate 1 • · · 30 Ethyl 4,6-dichloroindole-2-carboxylate

To a solution of ethyl pyruvate (2.05 mL) in absolute ethanol (38 mL) was added concentrated sulfuric acid (0.5 mL) with vigorous stirring. The resulting mixture was stirred at 23 ° C for 10 minutes, then 3,5-dichlorophenyl -? -? - 106,108,198 hydrazine hydrochloride (4 g) was added portionwise. The mixture was refluxed for 4 hours, cooled to 23 ° C, poured into cold water (500 mL) and extracted with diethyl ether (3 x 300 mL). The organic layers were separated and dried.

The solvent was evaporated under reduced pressure to give 2- (3,5-dichlorophenylhydrazone) -propionic acid ethyl ester as a yellow solid (5 g; tic DCM, Rf = 0.79, 0.47) as a mixture of E and Z isomers. The solid was added to polyphosphoric acid (20 g) with stirring and the mixture was heated for 20 minutes at 45 ° C to give a brown product which was crystallized with 95% ethanol (300 mL) to give the title compound as a tan solid (3 g). , 3 g; mp 180 ° C; those in DCM, R f = 0.54).

IR (CDCl3) νmax (cm -1) 3440 (NH), 1772-1709 (C = 0). Intermediate 2

Ethyl 3-formyl-4,6-dichloroindole-2-carboxylate

A solution of N-methylformanilide (5.19 g) and phosphorus oxychloride (5.53 g) was stirred at 23 ° C for 15 minutes. 1,2-Dichloroethane (60 ml) and Intermediate 1 (6 g) were added and the resulting suspension was stirred at 80 ° C for 6 hours. The reaction mixture was poured into 50% aqueous sodium acetate (300 mL) to give the title compound as a yellow solid (4.1 g; tic EA / CH, 4: 6, Rf = 0). 4).

··· Intermediate 3 · 2 «• j. Ethyl 3-formyl-1- (2-trimethylsilyl-ethoxymethyl-4 ·, ·, · · · · · · · · · · · · · · · · · · · · · (700mg) in dry DMF (20ml) at 0 ° C was added lithium bis-trimethylsilylamide (3.7ml, 1M solution in ♦ · ·; 1 in THF). The mixture was stirred for 15 minutes at 0 ° C, then trimethylsilyl ethoxymethylchloride 35 (0.817 g) was added. After 1 hour, the resulting mixture was poured into 2 x 19 6,6198 of water (25 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (950 mg) as a light yellow solid by filtration. R f = 0.3 EA / CH, 1: 9.

Intermediate 4

Ethyl 3- (2,2-dibromo vinyl) -1- (trimethylsilyl-ethoxymethyl) -4,6-dichloroindole-2-carboxylate Intermediate 3 (300 mg) was dissolved in dry dichloromethane (7 mL) and the solution was cooled to -15 ° C with an ice / salt bath. Then, triphenylphosphine (1.14 g) and carbon tetrabromide (719 ml) were added and the resulting solution was stirred for 1.5 hours, raising the temperature of the low-bogies to 0 ° C. Saturated NH 4 Cl solution (20 mL) was added, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried, concentrated and the resulting residue was passed through a pad of silica gel (CH / EA, 9: 1) to give the title compound (390 mg) as a yellow oil by filtration. R f = 0.62 CH / EA, 9: 1.

Intermediate 5

Ethyl 3-bromoethynyl-1- (2-trimethylsilyl-ethoxy-dimethyl) -4,6-dichloro-indole-2-carboxylate 4 !!! Intermediate 4 was dissolved in dry THF (50 mL), and the solution was cooled to 0 ° C in an ice / water bath. Li-1 · 2 · 1 · 2 thium-bis-trimethylsilylamide (7.6 mL, 1 M solution in THF) was added slowly via syringe, and the mixture was stirred for 30 minutes at 0 ° C, then saturated NH4Cl solution (20 mL) was added. Ethyl acetate was added to the mixture, the phases were separated and the organic layer was washed with: 3: 1N hydrochloric acid, dried and evaporated to dryness. The crude product was purified by flash chromatography to give the title compound (2.9 g) as a yellow oil. R f = 0.35 CH / EA, 95: 5.

3-Bromoethynyl-1- (2-trimethylsilyl-ethoxymethyl) -4- (3-bromoethynyl-1- (2-trimethylsilyl-ethoxymethyl) -4-? , 6-Dichloroindole-2-carboxylic acid Intermediate 5 (2.9 g) was dissolved in 95% ethanol (40 mL) and LiOH.H2O was added to the solution and stirred overnight at 80 ° C. . The reaction mixture was then evaporated to dryness and the resulting residue was washed with 1N hydrochloric acid. After filtration, the resulting solid was washed with water and dried over P2O2 to give the title compound (2.6 g) as a white solid.

IR (nujol) νmax (cm -1) 1676 (C = 0), 1600 (C = C).

1 H-NMR (DMSO): 14.00 (s), 7.90 (d), 7.38 (d), 5.92 (s), 3.41 (t), 0.76 (t) , -0.13 (s).

Intermediate 7 Methyl x-3-phenylcarbamoylethynyl-1- (2-trimethylsilylethoxymethyl) -4,6-dichloroindole-2-carboxylate Intermediate 6 (454 mg) was dissolved in dry THF (15 mL) and the solution cooled. To -78 ° C. A solution of 20-t-butyllithium (1.3 mL, 1.7 M in hexane) was added slowly and the reaction mixture stirred for two hours. Phenyl isocyanate (0.12 mL) was added and the mixture was allowed to gradually warm to room temperature and stirred for 3 hours. To the reaction mixture was added a saturated solution of NH4Cl-25 and extracted with ethyl acetate. Joined

IM

The organic phases were washed with 1N hydrochloric acid, water, and brine, dried and evaporated to dryness. The crude product was dissolved in dichloromethane (8 mL) and methanol (2 mL) and treated with 30 Me 3 SiCHN 2 (1.2 mL, 1.0 M in hexane) at room temperature. After stirring for 30 minutes, the mixture was evaporated to dryness and the crude product was purified by flash chromatography (CH / EA, ··· 85: 5) to give the title compound (230 mg) as a yellow solid.

t · «• ·

I I I

Intermediate 8 (E) -ethyl-3- [2- (phenylcarbamoylethenylethyl) -1- (2-trimethylsilyl-ethoxymethyl) -4,6-dichloride. -xndole-2-carboxylate 5 To a cooled (0 ° C) solution of (E) -ethyl 3- [2- (phenylcarbamoylethylenethyl) -4,6-dichloroindole-2-carboxylate (300 mg) in dry DMF (25 mL) was added dropwise a solution of sodium bis-trimethylsilylamide (1 M; 0.0814 mL) The resulting mixture was stirred for 10 minutes at room temperature and then cooled to 0. Trimethylsilyl ethoxymethyl chloride (185 mg) ) was added and the reaction mixture was stirred for 1 hour at room temperature The resulting solution was poured into water (20 mL) and extracted with diethyl ether (3 x 15 mL) The organic phases were dried, evaporated in vacuo and the product isolated by chromatography on silica gel (CH / EA, 83:15). ) to give the title compound (311 mg) Rf = 0.35 CH / EA, 85:15.

Intermediate 9 Ethyl 3- [2- (phenylcarbamoyl) propenyl] -1- (2-trimethylsilyl-ethoxymethyl) -4,6-dichloroindole-2-carboxylate P, P-diethyl-2-phosphonopropanilide (644 mg) was dissolved in anhydrous DMF (10 mL) and the resulting solution was cooled to 0 ° C and treated with LiN (Me 3 Si) 2 · 2.3 mL of a 1.0 M solution in THF ) For 1.5 hours. Intermediate 3 (784 mg) dissolved separately in dry DMF (8 mL) was added to the mixture and stirring was continued overnight. The reaction was quenched by pouring the mixture into 50 mL of saturated NH 4 Cl solution. The aqueous phase was then extracted with ethyl acetate and the organic phase was washed with 1N hydrochloric acid, water, and brine, dried and concentrated. Final purification by flash chromatography gave the title compound (660 mg) as a white solid. R f = 0.35 CH / EA, 8.5: 1.5.

• · • · · · I I i {I 1 • 1 • «« · · • «« •

Example IA

22 01 06 98 (E) -ethyl 3- [2- (phenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylate DBU (319 mg) was added to a stirred suspension of phenylcarbamoyl triphenylphosphonium bromide (1). g) in acetonitrile (10 ml) under nitrogen. Stirring was continued at 0 ° C for 15 minutes, then Intermediate 2 (680 mg) was added and the mixture was refluxed for 6 hours. After dilution with dichloromethane (15 mL), the precipitate formed to form 10 was collected by filtration to give the title compound (380 mg; tic EA / CH, 3: 7, Rf = 0.5) as a white solid.

IR (nujol) νmax (cm -1) 3305-3288 (NH), 1678-1662 (C = 0), 1627-1601 (C = C).

1 H NMR (DMSO): 12.61 (s), 10.20 (s), 8.27 (d), 7.73 (d), 7.52 (d), 7.36-7.30 (m), 7.06 (m), 6.77 (d), 4.39 (g), 1.36 (t).

Example IB

(E) -ethyl 3- [2- (4-trifluoromethylphenylcarbamoyl-2-yl) ethenyl] -4,6-dichloroindole-2-carboxylate

To a stirred suspension of 4- (trifluoromethyl) phenylcarbamoylmethyltriphenylphosphonium chloride (0.99 g) in acetonitrile (10 mL) at 0 ° C was added. : DBU (0.3 g). Stirring was continued at 0 ° C for 25 min, then Intermediate 2 (0.56 g) was added and the mixture was refluxed for 8 hours. After the mixture was diluted with dichloromethane (20 mL), the precipitate formed was recovered by filtration to give the title compound. lane (0.6 g; EA / CH route, 4: 6, Rf = 0.49) as a solid.

IR (nujol) νmax (cm -1) 3310 (NH), 1676 (C = 0), 1632, 1612 ··· (C = C).

· · · · · · · · · · · · · · · · · · · · · ···

Example 1C

106198 (E) -ethyl 3- [2- (2-isopropylphenyl) carbamoyl-ethenyl] -4,6-dichloroindole-2-carboxylate

To a stirred suspension of 2- (isopropyl-5-phenyl) carbamoylphenylmethyltriphenylphosphonium chloride (0.83 g) in acetonitrile (10 mL) at 0 ° C under nitrogen was added DBU. Stirring was continued at 0 ° C for 20 minutes, then Intermediate 2 (0.5 g) was added and the mixture was refluxed for 4 hours. After dilution of the mixture with dichloromethane (20 mL), the precipitate formed was collected by filtration to give the title compound (340 mg; tic EA / CH, 4: 6, Rf = 0.53) as a white solid.

IR (nujol) νmax (cm -1) 3304 (NH), 1676, 1659 (C = 0).

15 Example ID

(E) Ethyl-3- [2- (2-nitrophenylcarbamoyl) etenyy-yl] -4,6-dichloro-indole-2-carboxylate

To a stirred suspension of 2- (nitrophenyl) carbamoylmethyltriphenylphosphonium chloride (0.75 g) in acetonitrile (10 mL) at 0 ° C under nitrogen was added DBU (238 mg). Stirring was continued at 0 ° C for 20 minutes, then Intermediate 2 (0.45 g) was added and the mixture was refluxed for 4 hours. After dilution of the mixture, *** the precipitate formed with dichloromethane (20 mL) was collected by filtration to give the title compound (420 mg; route EA / CH, 4: 6, Rf = 0.55) as a yellow solid. ♦ · * 1, as a solid.

• · · • 2i IR (nujol) vmax (cm cm¹) 3348 - 3308 (NH), 1672 (C = 0), 1607 - ··· 1590 (C = C), 1556 - 1346 (NO,).

·· «1

* · 1 1 30 Example IE

(E) -ethyl 3- [2- (2-methyl-4-methoxyphenylamino-4H, 4'-carbonyl) ethenyl] -4,6-dichloroindole-2-carboxylate. 1 To a stirred suspension of (2-methyl-4-methoxyphenyl) aminocarbonylmethyltriphenylphosphonium · · · · 35 chloride (0.998 g) in acetonitrile (15 mL) at 0 ° C under nitrogen 2 DBU (0.32 g) was added under 24 10 06 98. Stirring was continued at 0 ° C for 25 minutes, then Intermediate 2 (0.6 g) was added and the mixture was refluxed for 3 hours. After dilution of the mixture with dichloromethane (20 mL), the precipitate formed was collected by filtration to give the title compound (0.57 g; tic EA / CH, 4: 6, Rf = 0.34) as a white solid.

IR (nujol) νmax (cm -1) 3302-3246 (NH), 1678-1659 (C = 0), 1624 (C = C).

Example 1F

(E) Ethyl-3- [2- (2-hydroxyphenylaminocarbonyl) ethenyl] -4,6-dichloro-indole-2-carboxylate

To a stirred suspension of (2-hydroxyphenyl) aminocarbonylmethyltriphenylphosphonium chloride (0.94 g) in acetonitrile (15 mL) at 0 ° C was added DBU (0.32 g) under nitrogen. Stirring was continued at 0 ° C for 25 minutes, then Intermediate 2 (0.6 g) was added and the mixture was stirred for 24 hours at room temperature. The suspension was evaporated to dryness and the residue was purified by flash chromatography (EA / CH, 3: 7 then 4: 6) to give the title compound (0.37 g; route EA / CH, 4: 6, Rf = 0.39). as a beige solid.

IR (nujol) vmax (cm -1) 3317-3290 (NH), 1678-1655 (C = 0), '···. 1618 (C = C).

• «

Example 1G

«Γ! (E) -ethyl 3- [2- (3,4-dimethoxyphenylaminocarbonyl-4-yl) ethenyl] -4,6-dichloroindole-2-carboxylate ··· ···· (3,4-Dimethoxyphenyl) amino-4-carbonylmethyltriphenylphosphonium chloride (0.69 g) in acetonitrile (10 mL) at 0 ° C under nitrogen was added DBU (0 21 g). Stirring was continued at 0 ° C for 25 minutes, then Intermediate 2 (0.4 g) was added and the mixture was stirred for 1-1; overnight at room temperature and then refluxed for 3 hours. After the mixture was diluted with dichloromethane, the precipitate formed was filtered off by filtration (20 mL). to give the title compound (0.457 g; tic EA / CH, 4: 6, Rf = 0.20) as a yellow solid.

IR (nujol) νmax (cm -1) 3317-3254 (NH), 1678 (C = O), 1620-1600 (C = C).

5 Example 1H

(E) Ethyl-3- [2- (4-Ethoxyphenylaminocarbonyl) ethenyl] -4,6-dichloro-indole-2-carboxylate

To a suspension of (4-ethoxyphenyl) aminocarbonylmethyltriphenylphosphonium chloride (0.67 g) in acetonitrile-10 (10 mL) at 0 ° C under nitrogen was added DBU (0.21 g). Stirring was continued at 0 ° C for 25 minutes, then Intermediate 2 (0.6 g) was added and the mixture was refluxed for 28 hours. After dilution of the mixture with dichloromethane (20 mL), the precipitate formed was collected by filtration to give the title compound (0.265 g; route EA / CH, 4: 6, Rf = 0.41) as a light yellow solid.

IR (nujol) νmax (cm -1) 3321-3260 (NH), 1676 (C = O), 1622 (C = C).

Example 11 (E) -ethyl 3- [2- (2,4-difluorophenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-carboxylate

To a suspension of (2,4-difluorophenyl) aminocarbonylmethyltriphenylphosphonium chloride (0.655 g)

I I I

In acetonitrile (10 mL) at 0 ° C under nitrogen was added DBU (0.21 g). Stirring was continued at 0 ° C for 25 minutes, then Intermediate 2 (0.4 g) was added and the mixture was refluxed for 26 hours. After dilution of the mixture, the precipitate formed with dichloromethane (20 ml) was recovered

IM

V 1 by filtration to give the title compound (0.42 g; route EA / CH, 4: 6, R f = 0.54) as a light yellow solid.

Ml · ’2 · IR (nujol) vmax (cm cm¹) 3298 (NH), 1678 - 1661 (C = 0), 1624 !:! (C = O.

I I I

«· · • III I 1 • ·« I 1 • · «« · • I I • · · · 2

• M

• ·

Example 1J

26 01 06 98 (E) -ethyl 3- [2- (2-fluoro-5-nitrophenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-carboxylate

To a suspension of (2-fluoro-5-nitrophenyl) -5-aminocarbonylmethyl-triphenyl-phosphonium chloride (0.52 g) in acetonitrile (10 mL) at 0 ° C under nitrogen was added DBU (0.16 g). Stirring was continued at 0 ° C for 25 minutes, then Intermediate 2 (0.3 g) was added and the mixture was refluxed for 18 hours. After dilution of the mixture with dichloro-10-rimethane (20 mL), the precipitate formed was collected by filtration to give the title compound (0.34 g; tic EA / CH, 4: 6, Rf = 0.41) as a beige solid.

IR (nujol) νmax (cm -1) 3300 (NH), 1680-1666 (C = 0), 1545-15 1377 (NO 2).

Example 2A

(E) -3- [2- (phenylcarbamoyl) ethenyl] -4,6-dichloro-ri-indole-2-carboxylic acid

To a solution of the compound of Example IA (250 mg) in ethanol (2.5 mL) was added lithium hydroxide (104 mg) at 23 ° C. The reaction mixture was stirred for 6 hours at 50 ° C and then the solvent was evaporated and the residue was dissolved in water (5 ml). The aqueous layer was made acidic · · · · · S with 1N hydrochloric acid until white: ***: 25 solid precipitate formed. This was collected by filtration and dried to give the title compound as a white solid (230 mg).

IR (nujol) νmax (cm-1) 3402-3281 (OH, NH), 1661 (O = 0), ". I 1607-1579 (C = C).

¹ · ′ ** ¹³ ^-NMR (DMSO): 12.4 (s), 10.1 (s), 8.50 (d), 7.74 (d), 7.48 (s), 7.27 (t), 7.16 (s), 7.11 (d), 6.99 (t).

The following compounds were prepared using the same general procedure: · · · '... ·

I 4 I

• I I I I I

• «« «•« «« «« «• ·« · · • • • • • •

Example 2B

106198 (E) -3- [2- (trifluoromethylphenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid Starting from Example IB (585-5 mg), the title compound was obtained as a light brown solid (520 mg). .

IR (nujol) νmax (cm -1) 3430-3000 (NH, OH), 1700-1678 (C = 0), 1636-1614 (C = C).

1 H-NMR (DMSO): 14-13.5 (s), 12.55 (s), 10.54 (s), 8.37 (d), 7.91 (d), 7.67 (d) ), 7.48 (d), 7.30 (d), 6.86 (d).

Example 2C

(E) -3- [2- (2-Isopropyl-phenylcarbamoyl) -ethenyl] -4,6-dichloro-indole-2-carboxylic acid, dithium salt Starting from the compound of Example 1C (317 mg), the title compound was obtained as a light brown solid (288 mg). .

IR (nujol) νmax (cm -1) 3661 (NH, OH), 1610 (C = 0).

1 H-NMR (DMSO): 12.1 (s), 9.39, (s), 8.57 (d), 7.57 (s), 7.38-7.28 (m), 7.28 - 7.10 (m), 3.25 (m), 1.15 (d).

Example 2D

(E) -3- [2- (2-Nitrophenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid Starting from the compound of Example ID (440 mg), the title compound was obtained as a yellow solid. 290 mg).

IR (nujol) νmax (cm -1) 3234 (NH, OH), 1684-1636 (C = 0), ··· 1639 (C = C).

• · · · 1 H-NMR (DMSO): 12.2 (s), 10.51 (s), 8.59 (d), 7.95 (dd),! ·: ·. 7.81 (dd), 7.69 (m), 7.48 (d), 7.38-7.28 (m), 7.20 (d).

»· ·

Example 2E

. ... (E) -3- [2- (2-methyl-4-methoxyphenylaminocarbonyl-4-yl) ethenyl] -4,6-dichloroindole-2-carboxylic acid. Starting from the compound of Example IE (0.54 g), the title compound was obtained as a yellow solid 35 (0.39 g).

«• •« · «2 2 8 8 8 2 8 106198 IR (nujol) vmax (cm'1) 3279 (NH, OH), 1703 - 1661 (C = 0). , 1630 (C = C).

1 H-NMR (DMSO): 12.41 (s), 9.39 (s), 8.26 (d), 7.48 (d), 7.36 (d), 7.27 (d). , 6.90 (d), 6.80 (d), 6.75 (dd), 3.73 δ (s), 2.19 (s).

Example 2F

(E) -3- [2- (2-Hydroxyphenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid Starting from the compound of Example IF (0.34 g), the title compound was obtained as a tan solid (0 , 33 g).

IR (nujol) νmax (cm -1) 3150 (NH, OH), 1736-1656 (C = O), 1630 (C = C).

1 H-NMR (DMSO): 12.56 (s), 9.97 (s), 9.76 (s), 8.24 (s), 7.8 (d), 7.49 (d) ), 7.30 (d), 6.96 (d), 6.96 (td), 6.88 (dd), 6.79 (td).

Example 26 (E) -3- [2- (3,4-Dimethoxyphenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-carboxylic Acid Starting from the compound of Example 1G (0.41 g), the title compound was obtained. as a light yellow solid (0.38 g).

IR (nujol)? Max (cm -1) 3420-2381 (NH), 1690-1680 (C = O),? 1620-1607 (C = C).

1 H NMR (DMSO): 13.8-13.6 (s), 12.53 (s), 10.08 (s), 8.23 (d), 7.47 (m), 7 29 (d), 7.20 (dd), 6.89 (d), 6.74 (d), • · 3.70 (s), 3.37 (s).

• · · ·

Example 2H

• «t ·% ·; ·. (E) -3- [2- (4-Ethoxyphenylaminocarbonyl) ethenyl] - »·«

4,6-Dichloroindole-2-carboxylic acid IV

... Starting from the compound of Example 1H (0.25 · · * ··· 1 g), the title compound was obtained as a light yellow • 1 ··· 1 solid (0.22 g).

IR (nujol) νmax (cm -1) 3248 (NH, OH), 1663 (C = O), 1632-351610 (C = C).

· · 9 9 · · «106 106 29 106198 1 H NMR (DMSO): 13.7 (s), 12.50 (s), 10.04 (s), δ , 22 (d), 7.61 (d), 7.47 (d), 7.29 (d), 6.86 (d), 6.74 (d), 3.97 (q), 1, 29 (t).

Example 21 5 (E) -3- [2- (2,4-Difluoro-phenylaminocarbonyl) -ethyl] -4,6-dichloro-indole-2-carboxylic acid Starting from the compound of Example 11 (0.41 g), the title compound was obtained. as a light yellow solid (0.37 g).

10 IR (nujol) νmax (cm -1) 3431-3233 (NH, OH), 1707-1678 (C = O), 1612 (C = C).

1 H NMR (DMSO): 14.0-13.6 (s), 12.54 (s), 9.99 (s), 8.29 (d), 7.97 (m), 7.48 ( d), 7.30 (m), 7.29 (d), 7.07 (m), 6.90 (d).

15 Example 3

Methyl 3- [2- (phenylcarbamoyl) ethynyl] -4,6-dichloroindole-2-carboxylate Intermediate'7 (2.9 g) was dissolved in 95% ethanol (18 mL) followed by hydrochloric acid ( 18 ml; 5 N) was added dropwise and the solution was refluxed for 3 hours. After addition of ethyl acetate (50 mL), the phases were separated and the organic phase was washed with water (2 x 40 mL), dried and purified by chromatography.

The resulting white solid (140 mg) was dissolved in THF (25 mL) and water (2 mL) and the solution was stirred for 10 minutes at room temperature. After cooling to 8 ° C, LiOH.H 2 O (42 mg) was added and the resulting mixture was stirred for 1 hour, poured into 0.01 N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated under reduced pressure to give a residue which was triturated with ethyl acetate to give the title compound (100 mg · mg) as a white solid. Rf = 0.18 CE / EA, 70:30.

IR (nujol) νmax (cm -1) 3273 (NH), 2220 (C = C), 1686 (C = C),, ···, 35 1636 (C = 0).

«C C <(f 4 4 4 I ·« 4 · • · · 4 «· • · · · 30 1 06 1 98 ^ -NMR (DMSO): 13.5 (s), 10.71 (s)). , 7.68 (m), 7.52 (m), 7.40 (d), 7.35 (m), 7.11 (m), 3.96 (s).

Example 4 3- [2- (Phenylcarbamoyl) ethynyl] -4,6-dichloro-5-indole-2-carboxylic acid

A mixture of the compound of Example 3 (100 mg) in tetrahydrofuran (4 ml) and water (2 ml) and LiOH.H2O (39 mg) was stirred for 12 hours at 45 ° C. The mixture was then poured into water (15 mL) and a solution of hydrochloric acid 10 (0.05 M, 5 mL) was added dropwise with stirring. The resulting precipitate was collected by filtration to give the title compound as a yellow solid (63 mg); mp. 207 ° C.

IR (nujol) νmax (cm -1) 3169 (NH-OH), 2240 (C = C), 1745 (C = 0), 1661 (C = 0).

1 H-NMR (DMSO): 14.0 (s), 13.05 (s), 12.88 (s), 10.7 (s).

7.67 (d), 7.51 (d), 7.35 (d), 7.33 (m), 7.10 (m).

Example 5 (D, L) -trans-ethyl-3- [2- (2-phenylcarbamoyl) cyclopropyl] -4,6-dichloroindole-2-carboxylate (a) (D, L) - Trans Ethyl 3- [2- (2-phenylcarbamoyl) cyclopropyl] -1- (2-trimethylsilylethoxymethyl) -4,6-dichloroindole-2-carboxylate

To a mixture of intermediate 8 (0.1 g) and palladium (II) acetate (4 mg) in dichloromethane (10 ml) under nitrogen at 0 ° C was added a solution of diazomethane diethyl ether (8 mL, 0.125 M) with stirring. During the simultaneous gas evolution a black teaspoon of solid was obtained. The reaction mixture was stirred for 15 hours at room temperature and then the solvent and any remaining diazomethane were evaporated under a stream of nitrogen. Dichloromethane was added to the resulting residue which was filtered through celite and evaporated under reduced pressure. Purification by flash chromatography gave a mixture of starting material and title compound in a ratio of 0.3: 1 (86 mg) as a light yellow solid.

(b) (D, L) -Trans-Ethyl-3- [2- (2-phenylcarbamoyl) -cyclopropyl] -4,6-dichloroindole-2-carboxylic acid Hydrochloric acid (2 mL, 5 M) was added to Example 5a. (66 mg) in ethyl alcohol (2 mL; 95%) and the solution was refluxed for 2 hours. After cooling, the mixture was poured into cold water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried and the solvent evaporated under reduced pressure to give the title compound (tic CH / EA, 6: 4; R f = 0.32).

IR (nujol) νmax (cm -1) 3312 (NH), 1672 (C = O), 1648 (C = O), 1599 (C = C), 1535 (C = C).

1 H NMR (CDCl 3): 12.1 (s), 10.2 (s), 7.60 (d), 7.40 (d), 7.28 (t), 7.01 (m), 4.40 (m), 4.25 (m), 2.55 (m), 1.98 (m), 1.49 (m), 1.27 (t), 1.22 (m).

Example 6 (D, L) -trans-3- [2-phenylcarbamoyl) cyclopropyl] -20 4,6-dichloroindole-2-carboxylic acid Starting from the compound of Example 5b (40 mg) and LiOH, using the method of Example 2A. the general procedure was obtained as the title compound as a white solid (23 mg).

, &Lt; 25 IR (nujol) νmax (cm -1) 3271 (NH, OH), 1663-1653 (0 = 0), I '. 1559 (C = C).

• · · * · *; * 1 H-NMR (DMSO): 13.4 (s), 11.98 (s), 10.11 (s), 7.60 (s), «· · ··· 7 , 37 (d), 7.27 (t), 7.17 (d), 7.00 (t), 1.97 (m), 1.50 (m), 1.47 (m), 1, 2 (m).

• · · V * 3 0 Example 7

Ethyl 3- [2- (phenylcarbamoyl) propenyl] -4,6- ···: dichloroindole-2-carboxylate · * ": Intermediate 9 (660 mg) was dissolved in 95% ethanol (6 mL). ) and refluxed in 5N hydrochloric acid 35 (6 mL) overnight The solution was dissolved in ethyl acetate, washed with 32 106198 After purification by column chromatography, the title compound (220 mg) was obtained as a white solid, Rf = 0.30 CH / EA, δ 7.5: 2.5.

1 H-NMR (DMSO): 12.48 (s, 1H), 9.70 (s, 1H), 7.80-7.72 (m, 3H), 7.48 (d, 1H), 7.33 (t, 2H), 7.26 (d, 1H), 7.08 (m, 1H), 4.32 (q, 2H), 1.79 (d, 3H), 1.30 (t, 3H) ppm; 10 IR (nujol) νmax (cm -1) 3317-3288 (strong NH), 1678 (strong C = 0).

Example 8 3 - [(2-Phenylcarbamoyl) propenyl] -4,6-dichloroindole-2-carboxylic acid The compound of Example 7 (210 mg) was dissolved in 95%. ethanol (6 mL) and the solution treated with LiOH.H 2 O (32 mg) for 1.5 days at 30 ° C and room temperature for 2.5 days. The solution was evaporated to dryness and treated with 1N hydrochloric acid for two hours. The white precipitate of Form-20 was filtered, dried under high vacuum and then recrystallized from diethyl ether to give the title compound (135 mg) as a white solid.

1 H-NMR (DMSO): 13.5 (s, 1H), 12.37 (s, 1H), 9.70 (s, 1H), 7.76 (d, 2H). , 7.75 (s, 1H), 7.45 (d, 1H), 7.31 (t, 2

(I

H), 7.23 (d, 1H), 7.06 (t, 1H), 1.78 (d, 3H) ppm; • ♦ IR (nujol) vmax (cm -1) 3209 (strong NH), 1664 (strong ··· »c = o).

* ... Example 9 • · · · · 4 * 30 (E) -3- [2- (phenylcarbamoyl) ephenyl] -4,6-dichloroindole-2-carboxylic acid, sodium salt · · * ··· 1 methanol was added dropwise to a suspension of • • 4 (E) -3- [2- (phenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid (200 mg) in 0.5 M sodium hydroxide, ··· , In 35 bridging solution (1.01 mL) until a clear solution was obtained. After stirring for 15 minutes, the 33 106198 solutions were evaporated to dryness and the residue was dried for 12 hours at 50 ° C to give the title compound. of the compound as a white solid (150 mg).

IR (nujol) νmax (cm -1) 3404-3126 (NH), 1624 (C = O), 1600 (C = C).

1 H-NMR (DMSO): 11.9 (s), 10.06 (s), 8.59 (d), 7.75 (d), 7.44 (d), 7.27 (t), 7 , 21 (d), 7.10 (d), 6.98 (t).

Example 10 10 (E) -3- [2- ((, Ν-Diethylamino) ethyl] -3- [2- (phenylaminocarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylate (E) ) -3- [2- (Phenylcarbamoyl) ethenyl] -4,6-dichloro-indole-2-carboxylate (0.3 g) and N, N-diethylethanol-15-amine (1.3 g) were stirred for 20 minutes. before sodium carbonate (0.078 g) was added and the mixture was heated for 24 hours at 70 ° C. The solution was concentrated in vacuo and the residue left overnight to give a white precipitate. Filtration and crystallization from ethyl 20 acetate gave the title compound (0.13 g;

R f = 0.65 DCM / MeOH, 8: 1) as a white solid.

IR (nujol) νmax (cm -1) 3300 (NH), 1676 (C = O), 1624 (C = C). 1 H NMR (DMSO): 12.52 (s), 10.18 (s), 8.22 (d), 7.70 (d), 7.50 (d), 7.32 (d), 7 , 31 (t), 7.04 (t), 6.73 (d), 4.36 • t 25 (t), 2.75 (t), 2.49 (q), 0.90 (t) ).

• «·

Example 11 · · · (E) - [2- (4- (2'-N-Morpholino) ethyl] -3- [2- (phenylaminocarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid - * ::: Plate • A mixture of (E) -3- [2- (phenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylate (400 mg). 4- (2-hydroxyethyl) morpholine (7 mL) and p-toluenesulfonic acid (15 mg) were stirred for 120 hours at 130 [deg.] C. The mixture was then diluted with water and extracted with ethyl acetate. 35 L (3 x 100 mL) The organic extracts were dried, concentrated, and the precipitate was collected to give the title compound. as a white solid (110 mg; Rf = 0.51 DCM / MeOH, 9: 1; mp 266-267 ° C).

1 H-NMR (DMSO): 10.21 (s), 8.28 (d), 7.75 (d), 7.56 - 7.35 δ (dd), 7.35 (t), 7.08 (t), 6.74 (d), 4.46 (t), 3.54 (m), 2.43 (m), 2.70 (t).

Example 12 (a) (E) -2- (t-Butylcarbonyloxymethyl) -3- [2- (phenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-10 carboxylate

The compound of Example 2 (200 mg) was dissolved in DMF (4 mL) and tetrabutylammonium chloride (168 mg) was added. After stirring for 0.5 hour, chloromethyl pivalate (118 mg) was added dropwise and the mixture was stirred for 48 hours at room temperature. The mixture was then diluted with water and extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with brine, dried and evaporated to give the crude product which was purified by flash chromatography to afford the title compound as a yellow solid (190 mg); mp. 205 ° C.

IR (nujol) νmax (cm -1) 3383-3308 (NH), 1747 (C = 0), 1688 (C = 0), 1634-1603 (C = C).

1 H-NMR (DMSO): 12.75 (s), 10.22 (s), 8.22 (d), 7.73 (d),? (25 7.54 (d), 7.36). (d), 7.33 (t), 7.07 (t), 6.79 (d), 6.02 (s), 1.15 (s).

Using the same general procedure, the following compounds were prepared: (b) (E) -2- [1- (Tetrahydro-4-pyran-4-yloxy-carboxyl)]. 1,30-yloxy) ethyl] -3- [2- (phenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-carboxylate • · ·, 5: From the compound of Example 2 (200 mg) in dry DMF: (11 ml), benzyltriethylammonium chloride s' ··· (178 mg) and 1- (tetrahydro-4H-pyran-4-yloxycarbonyl-oxo-· 35 Si) ethyl chloride (244 mg) were obtained when the mixture was stirred. 35 106198 at room temperature for four days at room temperature as a yellow solid (209 mg) / m.p. 209 ° C.

IR (nujol) νmax (cm -1) 3300 (NH), 1749 (C = 0), 1730 (C = 0). 1 H-NMR (DMSO): 12.73 (s), 10.22 (s), 8.21 (d), 7.72 (d), δ 7.53 (d), 7.34 (d) ), 7.32 (t), 7.05 (t), 6.90 (q), 6.76 (d), 4.76 (m), 3.72 (m), 1.87-1. 53 (m), 1.61 (d).

(c) (E) -2- [1- (Cyclohexyloxycarbonyloxy) ethyl) -3- [2- (phenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-carboxylate From the compound of Example 2 (300 mg). dry DMF (8 mL), benzyltriethylammonium chloride (178 mg) and 1- (cyclohexyloxycarbonyloxy) ethyl chloride (242 mg) were obtained after stirring at room temperature for 0.5 h as the yellow solid (170 mg); mp. 125 ° C.

IR (nujol) νmax (cm -1) 3300 (NH), 1730 (C = 0).

1 H-NMR (DMSO): 12.71 (s), 10.21 (s), 8.21 (d), 7.71 (d), 7.51 (d), 7.36-7.26 ( m), 7.05 (t), 6.85 (q), 6.76 (d), 4.54 (m), 1.79 (m), 1.51-1.1 (m), 1.6 (d).

20 (d) (E) -2 - [(Methoxycarbonylmethyl) -3- [2- (phenylaminocarbonyl) ethenyl] -4,6-dichloroindole-2-carboxylate

The compound of Example 2 (200 mg) in dry DMF (4 mL), tetrabutylammonium chloride (168

I I I

25 mg) and methyl chloroacetate (85 mg) were obtained after stirring for 48 hours at room temperature to give the title compound as a white solid (210 mg); mp. 241 - · · · 242 ° C.

· ♦ 1: 1 IR (nujol) νmax (cm'¹) 3348 (NH), 1749 (C = 0), 1672 (C = 0), · · · V: 30 1634 - 1610 (C = C).

1 H-NMR (DMSO): 12.8 (s), 10.21 (s), 8.28 (d), 7.72 (d), 7.54 (d), 7.38-7.28 (m) , 7.06 (t), 6.48 (d), 5.02 (s), • · 1 · 1: 3.73 (s).

• t · • «· i» 1 1 • • • • • • • • • •••••• 36 106198

Pharmaceutical Examples A. Capsules / Tablets

Active substance 200.0 mg Starch 1500 32.5 mg 5 Microcrystalline cellulose 60.0 mg

Croscarmellose Sodium 6.0 mg

Magnesium stearate 1.5 mg

The active ingredient was mixed with other excipients. The mixture may be used to fill gelatin capsules or compress tablets using suitable punches. The tablets may be coated using conventional techniques and coatings.

15 B. Tablets

The active ingredient is 200.0 mg

Lactose 100.0 mg

Microcrystalline cellulose 28.5 mg

Povidone 25.0 mg Croscaramellose sodium 6.0 mg

Magnesium stearate 1.5 mg

The active ingredient was mixed with lactose, a microcrystalline ···. with its cellulose and some croskaramel lozenges. Mixture • · • · · / ··. The granules were granulated with povidone when dispersed in a suitable solvent (i.e. water). When the granulate was dry, the granulate was mixed with the remaining fillers and dried. The mixture may be compressed using suitable punches ··· ♦ • and tablets may be coated using conventional ··· ♦ methods and coatings.

«M

• • • • 1 1 1 1 1 • · «1 1 • t t t t t t 1 1 1 1 t t t t t 1 t t t t t t t t t t t t t t t t · • ♦ 37 1 06 1 98 C. Injection formulation

The active ingredient is 0.1 to 7.00 mg / ml

Sodium phosphate 1.0 - 50.00 mg / ml

NaOH qs to achieve desired pH (3 to 10) water for injection qs 1 ml

The formulation can be packaged in glass (ampoules) using rubber stoppers (containers, syringes) and plastic / metal-10 li coatings (glass containers only).

D. Dry powder to be mixed with a suitable solvent

Active ingredient 0.1-100.00 mg Mannitol qs 0.02-5.00 mg

Packed in glass containers using rubber stoppers and plastic / metal coatings (glass containers only).

E. Inhalation Injections mg / cartridge

Active ingredient (micronised) 5.00

Lactose qs 25.00 «« <<* 1 ;;; The active substance, the micron, is finely divided into fine particles in the fused energy mill before being mixed with conventional lactose lactose in a high energy mixer. The powder mixture is filled into suitable unit dose containers as blister packs or capsules for use in a suitable inhaler or nebulizer device.

The compounds of the invention have an affinity for Str. to glycine binding site ···. 2 ·. was determined using the method described by Kishimoto H. et al. J. Neurochem 1981, 37 1015 - 1024.

• · • λ λ λ λ λ 1 1 1 1 1 2 2 2 2 38 38 38 38 1 1 38 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

The pKi values obtained with representative compounds of the invention are shown in the following table.

Ex. PKi 5 2a 8.5 2f 8.4 2g 8.1 2h 8.3 10 2 '8? 3 2j 8.0 7.7 8 8.32 15 The ability of the compounds of the invention to inhibit NMDA-induced seizures in the mouse was determined using the method described by Chiamulera et al. Psycho-Pharmacology (1990) 102, 551-552. In this assay, the ability of a compound to inhibit generalized seizure induced by intracerebroventricular injection of NMDA in a mouse was determined at several different dose levels. From these results, the dose needed to protect 50% of the animals from the effects of NMDA seizures was determined. This, expressed as 25 mg / kg, is called the ED50 value.

* * ϊ, saatu.ϊ Representative *: * results obtained with the compounds of the invention are shown in the following table.

····

III

····

Eg ED50 mg / kg 30 no iv after 1a 0.7 0.3-1 4 0.43 3: T: 9 0.6 5.98 35 11 0.3 3.2 Λ 12 03 10 • · · / • * · 4 · • · ♦ · · I »l • · 39 106198

The crude compounds of the invention are substantially non-toxic at therapeutically useful doses. Thus, for example, the compound of Example 9 did not produce any adverse reaction when administered to rats and mice at doses of 3 to 30 mg / kg intravenously or 30 to 300 mg / kg orally.

• «a • 4 • a 4 • I« aa 4 aa · • • • • • • • • • • · · · · · · ····························································• aa • · • M • • a · • a · aa * a • aa • a • a • aa a • aa aaaa • a · aa aa

Claims (10)

40 1 06 1 98 A process for the preparation of therapeutically useful 3-substituted 2-carboxyindole derivatives of the formula Cl I ACONHR 2 R - / (I) H wherein A is an ethynyl, ethenyl, 1-methylethenyl or cyclopropyl group; and R 2 is a phenyl group optionally substituted with up to three substituents selected from halo, C 1-4 alkyl, C 1-4 alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, nitro, SO 2 R 1 and COR R 1 is hydroxy, methoxy, or amino, and when more than one substituent is present, these may be the same or different, or their physiologically acceptable salts or their metabolically labile esters, characterized in that: »»! .V (a) for the preparation of compounds of the formula I in which A is an ethenyl or 1-methylethenyl group, a compound of the formula • t »» * «· V: Cl JL OHO I (II) • · I !:! C 1 - 2 - 3 N 4 - 4 CO 2 R 4 »MUZ 0 <* $ n I« «I · wherein R 3 is a carboxyl protecting group is reacted with a compound of the formula • ·« «·« Il • «106198 (R 5 ) 3 P = CHCONHR 2 (III) wherein R 5 is an alkyl or phenyl group and R 2 is as defined above or with a compound of formula 9e I (iv) (R 70) 2 op = c-CONHR 2 wherein R 7 is C 1-4 alkyl, R 6 is hydrogen or methyl and R 2 is as defined above, (b) for the preparation of compounds of formula I wherein A is a cyclopropyl group, an olefin of formula X / CHaCH-II (v) C 1 -C 3 - (CO 2) R 5 CH 2 O (CH 2) 2 Si (CH 3). 3 where R3 is a carboxyl protecting group, is reacted with a "" diazo derivative of the formula <t <N2 = CHCONHR2 (VI) wherein R2 is as defined above, followed by removal of the trimethylsilyl ethoxymethyl group. «(C) for the preparation of compounds of the formula I in which A is an ethynyl group, a bromic acid of the formula Cl 1 = CHBr ΓΊΐ- {: · Γ: JL 1 1 (IX) V ·; CH 2 O (CH 2) 2 Si (CH 3) 3 • 106 106 are reacted with an isocyanate of the formula r 2 nco wherein R 2 is above as defined, in the presence of a base, the product obtained is then treated with trimethylsilyldiazo-5-methane, and the trimethylsilyl ethoxymethyl group is removed by treatment with hydrochloric acid and then with a base, followed by (i) removal of the carboxyl protecting group if desired or necessary; and / or (ii) converting the resulting compound of formula I or a protected derivative thereof into a salt or metabolically labile ester thereof; and / or (iii) converting a compound of formula I or a protected derivative thereof into another compound of formula I or a protected derivative thereof. Process according to Claim 1, characterized in that a compound is prepared wherein R 2 is phenyl. Process according to Claim 1 or 2, characterized in that a compound is prepared wherein A 20 is ethynyl or 1-methylethenyl in the trans configuration. Process according to claim 1 or 2, characterized in that a compound is prepared wherein: V: A is unsubstituted ethenyl. • · · ί · Process according to claim 4, characterized in that a compound is prepared wherein the unsubstituted ethenyl is in the trans configuration and R 2 · · · is a phenyl group substituted by one or two substituents selected from fluorine, trifluoromethyl, methyl, • · '··· * l, isopropyl, hydroxy, methoxy, ethoxy or nitro. «♦« «♦ ... * 30 Process according to Claim 1, characterized in that (E) -3- [2- (phenyl- * * - licarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid is prepared. acid, a physiologically acceptable salt thereof, or a metabolically labile ester thereof. • · • * ♦ • 1 »•» «106198 Process according to claim 6, characterized in that the product is isolated as a sodium salt. Process according to claim 1, characterized in that 3- [2- (phenylcarbamoyl) propenyl] -4,6-dichloroindole-2-carboxylic acid, a physiologically acceptable salt or a metabolically labile ester thereof is prepared. . Process according to claim 1, characterized in that (E) -3- [2- (phenylcarbamoyl) ethynyl] -4,6-dichloroindole-2-carboxylic acid, a physiologically acceptable salt or metabolite thereof is prepared. - six labile esters. Process according to claim 1, characterized in that (E) -3- [2- (4-ethoxyphenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid is prepared; (E) -3- [2- (2-hydroxy-5-nitrofenyylikarbamoyy-yl) ethenyl] -4,6-dichloro-indole-2-carboxylic acid; (E) -3- [2- (2-Methyl-4-methoxyphenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid; ···. (E) -3- [2- (2-Isopropyl-phenylcarbamoyl) -ethenyl] -butyl; li] -4,6-dichloroindole-2-carboxylic acid; N, N * - (E) -3- [2- (2,4-Difluorophenylcarbamoyl) ethyl] - (N, N ') -4'-dichloroindole-2-carboxylic acid; or? · · · ♦ ·· (E) -3- [2- (3,4-Dimethoxyphenylcarbamoyl) ethenyl] -4,6-dichloroindole-2-carboxylic acid; and a physiologically acceptable salt and a metabolically labile ester thereof. • * «♦ · ··· • · •« · ♦ · ♦ «<« <<«« <«4 ·« · · · · · · 44 1 06 1 98